This invention relates to synthesis of decaborane. More particularly, the invention relates to an integrated process of synthesizing decaborane from boric acid such that at least about 90%, and preferrably all, of the boron atoms in the decaborane molecule are the .sup.10 B isotope.
Application of neutrons for radiotherapy of cancer has been a subject of considerable clinical and research interest since the discovery of the neutron by Chadwick in 1932. Fast neutron radiotherapy was first used by Robert Stone in the Lawrence Berkeley Laboratory in 1938. This technology has evolved over the years to the point where it is now a reimbursable modality of choice for treatment of inoperable salivary gland tumors, and it is emerging on the basis of recent research data as a promising alternate modality for treatment of prostate cancer, some lung tumors, and certain other malignancies as well. Neutron capture therapy (NCT), a somewhat different form of neutron-based therapy, was proposed in the mid 1930's and, despite some notable failures in early U.S. trials, has attracted a great deal of renewed research interest lately due to significant improvements in the relevant technology and radiobiological knowledge.
The basic physical processes involved in fast neutron therapy and neutron capture therapy differ in several respects. In fast neutron therapy, neutrons having relatively high energies (approximately 30-50 MeV) are generated by a suitable neutron source and used directly for irradiation of the "treatment volume," just as is done with standard photon (x-ray) therapy. In neutron capture therapy, a neutron capture agent, which in current practice is boron-10 (thus, boron neutron capture therapy or BNCT) is selectively taken into the malignant tissue following the administration of a suitable boronated pharmaceutical, preferably into the bloodstream of the patient. At an appropriate time after boron administration, the treatment volume is exposed to a field of thermal neutrons produced by application of an external neutron beam. The thermal neutrons interact with the boron-10 atoms, which have a very high capture cross section in the thermal energy range and, ideally, are present only in the malignant cells. Each boron-neutron interaction produces an alpha particle (.sup.4 He.sup.2+) and a lithium ion (.sup.7 Li.sup.3+) with about 2 MeV of kinetic energy distributed between these two heavy ion products. The translational range of these product ions is particularly short, about 7.6 .mu.m in photographic gelatin and about 1.1 cm in air. Consequently, the lithium ion and the .alpha.-particles are short-range, energetic species capable of imparting, through ionizing processes, immense local damage to organic materials, such as DNA, within a geometric volume that is comparable to the size a malignant cell. The .sup.11 B nucleus is incapable of undergoing a boron neutron capture reaction, while the effective cross section of .sup.10 B for boron neutron capture is 3837 barns (10.sup.-24 cm.sup.2). Ideally, cells that carry large numbers of .sup.10 B nuclei are subject to destruction by BNC, while neighboring cells that are free of .sup.10 B nuclei are spared.
Because boron is ideally taken up only in the malignant cells, the BNCT process offers the possibility of highly selective destruction of malignant tissue, with cellular-level separation of neighboring normal tissue since the neutron sources used for BNCT are themselves designed to produce a minimal level of damage of normal tissue. When BNCT is administered as a primary therapy, an epithermal-neutron beam (neutrons having energies in the range of 1 eV to 10 keV) is used to produce the required thermal neutron flux at depth, since these somewhat higher-energy neutrons will penetrate deeper into the irradiation volume before thermalizing, yet they are still not of sufficient energy to inflict unacceptable damage to intervening normal tissue.
A third form of neutron therapy, fast neutron therapy with neutron capture augmentation, is basically a hybrid that combines the features of fast neutron therapy and NCT. This procedure comprises introducing a neutron capture agent preferentially into the malignant tissue prior to the administration of standard fast neutron therapy. For example, B. R. Griffin & G. E. Laramore, WO 96/00113, showed that fast neutron therapy is significantly enhanced by irradiating target cells with fast neutrons in the presence of a boron neutron capture agent having preferably at least nine .sup.10 B atoms per molecule of the agent. Suitable boron capture agents disclosed by WO 96/00112 include those based on: polyhedral borane anion derivatives, derivatives that comprise two polyhedral borane anion cages linked together to form a structure comprising 20 boron atoms, polyhedral carboranes such as compounds of the formulas closo-C.sub.2 B.sub.n-2 H.sub.n, closo-CB.sub.n-1 H.sub.n.sup.-, or nido-C.sub.2 B.sub.n-3 H.sub.n.sup.-, oligomeric peptides constructed from boron-rich .alpha.-amino acids, or boron enriched oligophosphates.
Decaborane, B.sub.10 H.sub.14, due in part to its relative stability and its normally solid state, is one of the most useful of the boron hydrides. Moreover, decaborane is an essential precursor to many advanced pharmaceuticals useful in BNCT. Decaborane is, however, difficult to obtain commercially, explosive in combination with certain other compounds, and difficult to produce by known methods.
Prior to the late 1970's, the principal proposed processes for the preparation of decaborane involved pyrolytic or high pressure reactions using lower boron hydrides, such as diborane (B.sub.2 H.sub.6) or tetraborane (B.sub.4 H.sub.10). Processes of this type are disclosed in U.S. Pat. No. 2,987,377 to Faust et al.; U.S. Pat. No. 2,968,534 to G. F. Judd; and U.S. Pat. No. 2,989,374 to J. A. Neff. A non-pyrolytic method involving the reaction of an alkali metal pentaborane with diborane at temperatures below -20.degree. C. is disclosed in U.S. Pat. No. 3,489,517 to Shore et al. These methods all required elaborate equipment and potentially hazardous reagents.
U.S. Pat. No. 4,115,521 to G. B. Dunks et al. discloses an improved process wherein decaborane is prepared from a stable higher borohydride salt by a single step oxidation reaction using conventional oxidants at ambient room temperatures and ordinary atmospheric pressure and in ordinary chemical apparatus. This method consists of contacting and oxidizing the B.sub.11 H.sub.14.sup.- anion at a temperature between -10.degree. C. and 50.degree. C. with an oxidizing agent having an electrode potential (E.sub.o) of at least +0.6 volts. U.S. Pat. No. 4,153,672 and U.S. Pat. No. 4,115,520 to G. B. Dunks et al. further discloses a method of synthesizing the B.sub.11 H.sub.14.sup.- anion by heating a suspension of an alkali metal borohydride in a solvent and adding an alkyl halide. The Dunks patents do not teach methods for the production of .sup.10 B-enriched decaborane or its use as a precursor of BNCT pharmaceuticals, which require that at least about 90% of the boron atoms be .sup.10 B. Moreover, the Dunks patents also do not teach the conversion of .sup.10 B(OH).sub.3 to enriched decaborane via the precursors, Na.sup.10 BH.sub.4 and the Na.sup.10 B.sub.11 H.sub.14.
In view of the foregoing, it will be appreciated that providing an integrated process for synthesis of decaborane from boric acid such that all of the boron atoms are the .sup.10 B isotope would be a significant advancement in the art. Additional advancements in the art are obtained by means of improved methods of synthesizing the B.sub.11 H.sub.14 anion from an alkali metal borohydride, and converting the B.sub.11 H.sub.14 anion to decaborane.